Characterizing the Specificity of Class IIa Lysine Deacetylases
Abstract
PROJECT SUMMARY/ABSTRACT PI: Terry Watt Institution: Xavier University of Louisiana Title: Characterizing the specificity of class IIa lysine deacetylases Metal-dependent lysine deacetylases (KDACs) are multi-functional proteins that mediate control of numerous cellular processes. Acetylation and deacetylation of proteins have been directly associated with a wide range of biological processes, including metabolic regulation and organismal development as well as numerous diseases. Few specific substrates or indirect targets of KDACs have been identified despite widespread acetylation of proteins, which is a critical limitation in the ability to effectively regulate KDACs and their associated pathways. Class IIa KDACs have been reported to have regulatory roles in pain pathways and injury repair mechanisms, and so identifying their specific intracellular targets will provide new approaches for enhancing Soldier performance. However, to date there have been no reports of catalytic activity for class IIa KDACs with biologically relevant substrates, so direct evidence of a catalytic role for these enzymes is lacking. When compared to other KDACs, class IIa KDACs also contain an additional protein domain of unknown function. Our overarching hypothesis for this project is that class IIa KDACs are catalytically active in vivo, based in part on our recent discovery of several biologically relevant peptides that are active with a class IIa KDAC. Our objectives are to identify potential substrates of these enzymes and evaluate contributing factors to the catalytic activity. Our specific aims are to: (1) characterize the molecular determinants of interactions between class IIa KDACs and substrates; and (2) identify class IIa KDAC substrates in vivo. Regardless of whether all class IIa KDACs prove to be catalytically active as deacetylases in vivo, an understanding of their binding selectivity, interaction preferences, and contributions of the non-catalytic domain will clarify their biological functions. Key novel results will include demonstration of direct deacetylation with biologically relevant substrates, linking of model substrates to in vivo substrates, and determination of intracellular acetylation changes that are directly linked to catalytic activity by these enzymes. Although the class IIa KDACs have been identified as critical regulators of important biological processes, the mechanism through which they exert that effect has not been clear. Our work will provide significant insight into these mechanisms, enabling future work to more closely link the underlying biological mechanisms and organismal level effects. The detailed description of substrate interactions for each enzyme will aid in design of novel regulatory molecules. Identification of specific KDAC substrate proteins will also enable a path forward for understanding how acetylation modifies the behavior of those substrates. In total, this project will greatly expand our understanding of how KDACs function in vivo, and how the various specific functions of particular KDACs result in particular phenotypic outcomes at the cellular or organismal level. The results will enable follow-up studies on specific KDAC interactions and functional targets, and provide new approaches for development of specific regulatory molecules. As a whole, our results will provide new approaches for enhancing Soldier performance through regulation of critical biological pathways. Finally, the project will directly contribute to the research training of at least five undergraduate students per year. Students from predominantly underrepresented groups will make key contributions to all aspects of this project.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 21, 2019
- Source ID
- W911NF1810450
Entities
People
- Terry J Watt
Organizations
- Army Contracting Command
- Office of the Secretary of Defense
- Xavier University of Louisiana